Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque: Individual Participant Data Meta-Analysis of 20 Prospective Studies.

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.

Correction: Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

Normative values for carotid intima media thickness and its progression: Are they transferrable outside of their cohort of origin?

BACKGROUND: The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. DESIGN: Meta-analysis of individual participant data. METHOD: From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. RESULTS: Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. CONCLUSIONS: The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

Inflammatory markers and extent and progression of early atherosclerosis: Meta-analysis of individual-participant-data from 20 prospective studies of the PROG-IMT collaboration.

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population. METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses. RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p < 0.001); 0.0072 mm for fibrinogen (p < 0.001); and 0.0025 mm for leucocyte count (p = 0.033). 'Inflammatory load', defined as the number of elevated inflammatory markers (i.e. in upper two quintiles), showed a positive linear association with baseline CCA-IMT (p < 0.001). Longitudinal associations of baseline inflammatory markers and changes therein with CCA-IMT progression were null or at most weak. Participants with the highest 'inflammatory load' had a greater CCA-IMT progression (p = 0.015). CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

Carotid intima-media thickness progression and risk of vascular events in people with diabetes: results from the PROG-IMT collaboration.

OBJECTIVE: Carotid intima-media thickness (CIMT) is a marker of subclinical organ damage and predicts cardiovascular disease (CVD) events in the general population. It has also been associated with vascular risk in people with diabetes. However, the association of CIMT change in repeated examinations with subsequent CVD events is uncertain, and its use as a surrogate end point in clinical trials is controversial. We aimed at determining the relation of CIMT change to CVD events in people with diabetes. RESEARCH DESIGN AND METHODS: In a comprehensive meta-analysis of individual participant data, we collated data from 3,902 adults (age 33-92 years) with type 2 diabetes from 21 population-based cohorts. We calculated the hazard ratio (HR) per standard deviation (SD) difference in mean common carotid artery intima-media thickness (CCA-IMT) or in CCA-IMT progression, both calculated from two examinations on average 3.6 years apart, for each cohort, and combined the estimates with random-effects meta-analysis. RESULTS: Average mean CCA-IMT ranged from 0.72 to 0.97 mm across cohorts in people with diabetes. The HR of CVD events was 1.22 (95% CI 1.12-1.33) per SD difference in mean CCA-IMT, after adjustment for age, sex, and cardiometabolic risk factors. Average mean CCA-IMT progression in people with diabetes ranged between -0.09 and 0.04 mm/year. The HR per SD difference in mean CCA-IMT progression was 0.99 (0.91-1.08). CONCLUSIONS: Despite reproducing the association between CIMT level and vascular risk in subjects with diabetes, we did not find an association between CIMT change and vascular risk. These results do not support the use of CIMT progression as a surrogate end point in clinical trials in people with diabetes.

The role of prestroke glycemic control on severity and outcome of acute ischemic stroke.

Background/Aim. Relatively few studies have investigated the association of prestroke glycemic control and clinical outcome in acute ischemic stroke (IS) patients, regardless of presence of diabetes mellitus (DM). The aim of this study was to investigate the importance of prestroke glycemic control on survival, stroke severity, and functional outcome of patients with acute IS. Methods. We performed a retrospective survival analysis of 501 patients with IS admitted to Sahlgrenska University Hospital from February 15, 2005, through May 31, 2009. The outcomes of interest were acute and long-term survival; the stroke severity (NIHSS) and the functional outcome, mRS, at 12 months. Results. HbA1c was a good predictor of acute (HR 1.45; CI, 1.09 to 1.93, P = 0.011) and long-term mortality (HR 1.29; CI 1.03 to 1.62; P = 0.029). Furthermore, HbA1c >6% was significantly correlated with acute stroke severity (OR 1.29; CI 1.01 to 1.67; P = 0.042) and predicted worse functional outcome at 12 months (OR 2.68; CI 1.14 to 6.03; P = 0.024). Conclusions. Our study suggests that poor glycemic control (baseline HbA1c) prior to IS is an independent risk factor for poor survival and a marker for increased stroke severity and unfavorable long-term functional outcome.

Neuronal and glia-related biomarkers in cerebrospinal fluid of patients with acute ischemic stroke.

BACKGROUND: Cerebral ischemia promotes morphological reactions of the neurons, astrocytes, oligodendrocytes, and microglia in experimental studies. Our aim was to examine the profile of CSF (cerebrospinal fluid) biomarkers and their relation to stroke severity and degree of white matter lesions (WML). METHODS: A total of 20 patients (mean age 76 years) were included within 5-10 days after acute ischemic stroke (AIS) onset. Stroke severity was assessed using NIHSS (National Institute of Health stroke scale). The age-related white matter changes (ARWMC) scale was used to evaluate the extent of WML on CT-scans. The concentrations of specific CSF biomarkers were analyzed. RESULTS: Patients with AIS had significantly higher levels of NFL (neurofilament, light), T-tau, myelin basic protein (MBP), YKL-40, and glial fibrillary acidic protein (GFAP) compared with controls; T-Tau, MBP, GFAP, and YKL-40 correlated with clinical stroke severity, whereas NFL correlated with severity of WML (tested by Mann-Whitney test). CONCLUSIONS: Several CSF biomarkers increase in AIS, and they correlate to clinical stroke severity. However, only NFL was found to be a marker of degree of WML.

Heart dysfunction in patients with acute ischemic stroke or TIA does not predict all-cause mortality at long-term follow-up.

BACKGROUND: Despite heart failure being a substantial risk factor for stroke, few studies have evaluated the predictive value of heart dysfunction for all-cause mortality in patients with acute ischemic stroke, in particular in the elderly. The aim of this study was to investigate whether impaired heart function in elderly patients can predict all-cause mortality after acute ischemic stroke or transient ischemic attack (TIA). METHODS: A prospective long-term follow-up analysis was performed on a hospital cohort consisting of n = 132 patients with mean age 73 ± 9 years, presenting with acute ischemic stroke or transient ischemic attack, without atrial fibrillation. All patients were examined by echocardiography during the hospital stay. Data about all-cause mortality were collected at the end of the follow-up period. The mean follow-up period was 56 ± 22 months. RESULTS: In this cohort, 58% of patients with acute ischemic stroke or TIA had heart dysfunction. Survival analysis showed that heart dysfunction did not predict all-cause mortality in this cohort. Furthermore, in multivariate regression analysis age (HR 5.401, Cl 1.97-14.78, p < 0.01), smoking (HR 3.181, Cl 1.36-7.47, p < 0.01), myocardial infarction (HR 2.826, Cl 1.17-6.83, p < 0.05) were independent predictors of all-cause mortality. CONCLUSION: In this population with acute ischemic stroke or TIA and without non-valvular atrial fibrillation, impaired heart function does not seem to be a significant predictor of all-cause mortality at long-term follow-up.

Electrocardiographic abnormalities and elevated cTNT at admission for intracerebral hemorrhage: predictors for survival?

BACKGROUND: Cerebrovascular lesions are often associated with electrocardiographic (ECG) abnormalities. The main purpose of this work was to investigate the prognostic value of ECG abnormalities and/or elevated cardiac troponin (cTNT) on admission in patients with nontraumatic intracerebral hemorrhage (ICH). METHODS: Ninety-seven consecutive patients with ICH were included. The predictive value of ECG abnormalities and increased TNT on survival were evaluated using Cox proportional hazard model. RESULTS: The most frequently observed ECG abnormalities were the presence of a Q wave (39.6%), followed by prolonged QTc (>0.44 s; 35.4%), which was an independent predictor for long-term mortality (P = 0.019). No difference in QTc was observed between patients with right versus left ICH. Increased cTNT levels at admission had no prognostic value. CONCLUSION: Various ECG changes were common in patients presenting with an ICH, but only prolonged QTc was found to be an independent predictor of poor survival during follow-up after ICH.

The effect of statins on acute and long-term outcome after ischemic stroke in the elderly.

BACKGROUND: Although treatment with statins has produced beneficial effects when used as secondary prevention, its primary protective role is still somewhat controversial. Moreover, few studies have evaluated the effect of statins in older patients with stroke. OBJECTIVE: The aim was to investigate whether treatment with statins decreases stroke severity and/or improves survival and outcome after stroke in an older population. METHODS: We investigated the association between previous statin use and stroke severity (National Institutes of Health Stroke Scale [NIHSS]), as well as the effect of poststroke statin treatment on 12-month functional outcome (modified Rankin Scale [mRS] score) in 799 patients (mean age, 78 years), with acute ischemic stroke. The effect of statin treatment on survival was examined using the Cox proportional hazard model, after adjusting for relevant covariates. RESULTS: Statins did not decrease stroke severity and did not improve 30-day survival. However, both the 12-month survival (hazard ratio = 0.33; 95% CI, 0.20-to 0.54; P < 0.001) and the 12-month functional outcome (odds ratio = 2.09; 95% CI, 1.25-3.52; P = 0.005) were significantly better in the group treated with statins. CONCLUSIONS: Significantly better survival and functional outcome were noted with poststroke statins at the end of the 12-month follow-up period. Statins seem to provide beneficial effects for the long-term functional outcome and survival in the elderly.

Comparative evaluation of treatment with low-dose aspirin plus dipyridamole versus aspirin only in patients with acute ischaemic stroke.

BACKGROUND: Previous studies have suggested that pre-stroke treatment with low-dose aspirin (A) could reduce the severity of acute ischaemic stroke, but less is known on the effect of pre-stroke treatment with a combination of aspirin and dipyridamole (A + D) and post-stroke effects of these drugs. The aim of the present study was to evaluate the effect of this drug combination on acute and long-term prognosis of ischaemic stroke. METHODS: Patients without atrial fibrillation admitted to the stroke unit with acute ischaemic stroke (n = 554) or TIA (n = 108) were studied during acute hospital care and up to 12 months after discharge from hospital. RESULTS: Prior to acute stroke 62 patients were treated with A + D while 247 patients were treated with A only. No beneficial effects of the combination A + D compared to A only were noted on stroke severity and/or acute in-hospital mortality. However, survival analysis by Cox-proportional hazard model demonstrated lower 12-months all-cause mortality in patients discharged with A + D (n = 275) compared with patients on A only (HR, 0.52; CI, 0.32-0.86; p = 0.011; n = 262) after adjusting for age, baseline NIHSS, previous stroke, previous myocardial infarction and type 2 diabetes. We also noted a tendency towards lower all-cause mortality at 3 months with use of A + D, but this was not statistically significant (p = 0.12). CONCLUSIONS: Pre-stroke treatment with a combination of low-dose A + D does not reduce the severity of acute stroke, nor does it reduce the acute in-hospital mortality. However, treatment with A + D at discharge from hospital is seemingly associated with lower long-term mortality compared with A only, contrary to the results from previous randomised studies. However, our results must be interpreted with extreme caution considering the non-randomised study design.

Can prolonged QTc and cTNT level predict the acute and long-term prognosis of stroke?

BACKGROUND: Previous studies in patients with stroke indicate that QTc prolongation and elevated cTNT are related to increased risk of all-cause and cardiovascular mortality. METHODS: We analysed the importance of electrocardiographic (ECG) abnormalities and elevated serum cardiac troponin (cTNT)--at baseline examination--as potential predictors for acute and long-term mortalities after stroke in a follow-up of 478 patients with a mean age of 78 years. RESULTS: In a multivariate analysis, strong predictors for poor prognosis during the acute phase were: elevated cTNT (p=0.001); stroke severity (p=0.004); ischemia on ECG (p=0.044); and age (p=0.050). Prolonged QTc interval was on the limit to statistical significance (p=0.050) when using multivariate analysis, while clearly significant in a Cox-regression (when corrected for missing cTNT values). One year after stroke, when adjusted for covariates (gender, diabetes mellitus, hypertension, and ischemic heart disease), elevated cTNT (p=0.001), stroke severity (p=0.014), and age (p=0.031) retained a significant relation with mortality. Moreover, atrial fibrillation was strongly correlated with poor survival (p=0.009). Cox regression confirmed the predictive value of QTc, cTNT, age, and stroke severity, as markers of acute mortality in relation to stroke. CONCLUSION: Prolonged repolarization time independently predicts poor prognosis during the acute phase, but not one year after stroke. In the absence of acute myocardial infarction, elevated initial cTNT is strongly related to poor outcome, both during the acute phase and one year after stroke.

Apolipoprotein B/apolipoprotein A-I in relation to the metabolic syndrome and change in carotid artery intima-media thickness during 3 years in middle-aged men.

BACKGROUND AND PURPOSE: The apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio is a measure of the relationship between different lipoprotein particles and a powerful predictor of coronary death. The aim was to examine whether apoB/apoA-I was associated with the metabolic syndrome (MetS) at baseline and also with the future change in carotid artery intima-media thickness (IMT). METHODS: In 313 58-year-old men, carotid artery IMT was measured bilaterally by high-resolution B-mode ultrasound at baseline and after 3 years of follow-up. Serum apolipoprotein concentrations and the components of MetS were measured at study entry. RESULTS: ApoB/apoA-I showed statistically significant associations with body mass index, waist-to-hip ratio, high-density lipoprotein (HDL) cholesterol, triglycerides, low-density lipoprotein (LDL) particle size, insulin, and diastolic blood pressure. Two thirds of the patients with MetS had high apoB/apoA-I ratios (>0.90) compared with one third of those without the syndrome (P<0.001). The IMT change was associated with apoB, total cholesterol, LDL cholesterol, triglycerides, and inversely with HDL cholesterol and LDL particle size at entry, and there was a strong colinearity between these variables. The subjects with apoB/apoA-I above the first tertile (0.74) had a 20-microm-higher (95% CI, 7 to 33) annual increase in IMT compared with those below this level after adjustment for blood pressure and smoking. CONCLUSIONS: The apoB/apoA-I ratio was strongly associated with MetS and its components at baseline. ApoB/apoA-I at baseline was related to the change in carotid artery IMT during 3 years of follow-up. There was a strong colinearity between apoB/apoA and the atherogenic lipids.

Erythrocyte sodium/lithium countertransport is associated with thrombotic and fibrinolytic factors in 58-year-old men.

The metabolic syndrome, in which insulin resistance is the core feature, is associated both with dysregulation of thrombosis/fibrinolysis and erythrocyte sodium/lithium countertransport (SLC). To investigate this further we designed a cross-sectional study to examine whether factors involved in coagulation- and fibrinolysis systems were associated with SLC independently of insulin resistance in 93 58-year-old men. SLC was in univariate analysis positively correlated with PAI-1 activity (r = 0.35, p <0.01), tPA antigen (r = 0.38, p <0.01), von Willebrand factor (r = 0.25, p <0.05), protein S (r = 0.26, p <0.05), and C (r = 0.30, p <0.01), and negatively associated with tPA activity(r = -0.28, p <0.01). Since these correlations could be influenced by the components of the metabolic syndrome itself, a separate analysis with adjustment for glucose infusion rate (GIR), plasma insulin, body fat, sagittal diameter of the abdomen (SD) and log serum triglyceride concentration (TG) was conducted. Then SLC was associated with tPA antigen independent of GIR, plasma insulin, body fat, SD and TG. SLC was also associated with protein C independent of GIR, insulin, body fat and SD but not TG. In conclusion, we found a relationship between SLC and the fibrinolytic system that was not related to the metabolic syndrome.